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Evaluating the Regulatory Immunomodulation Effect of Irreversible Electroporation (IRE) in Pancreatic Adenocarcinoma

  • Harshul Pandit
  • Young K. Hong
  • Yan Li
  • Jack Rostas
  • Zachary Pulliam
  • Su Ping Li
  • Robert C. G. MartinEmail author
Pancreatic Tumors
  • 84 Downloads

Abstract

Background

Irreversible electroporation (IRE) has been demonstrated as an effective local method for locally advanced (stage 3) pancreatic adenocarcinoma. Immune regulatory T cells (Tregs) induce immunosuppression of tumors by inhibiting patients’ anti-tumor adaptive immune response. This study aimed to evaluate the immunomodulation effect of IRE to identify an ideal time point for potential adjuvant immunotherapy.

Methods

This study prospectively evaluated an institutional review board-approved study of patients undergoing either in situ IRE or pancreatectomy. Patient blood samples were collected at different time points (before surgery [preOP] and on postoperative day [POD] 1, POD3, and POD5). Peripheral blood mononuclear cells (PBMCs) were isolated and evaluated for three different CD4 + Treg subsets (CD25 + CD4 +, CD4 + CD25 + FoxP3 +, CD4 + CD25 + FoxP3 −) by flow cytometry and analyzed for median fold change (MFC) between each two consecutive time points (MFC = log2(T2/T1)).

Results

The study analyzed 15 patients with in situ IRE (n = 11) or pancreatectomy (PAN) (n = 4). In both groups, CD25 + CD4 + Tregs decreased on POD1 followed by a steady increase in pancreatectomy, whereas the trend in the IRE group reversed between D3 and D5 (MFC: IRE [− 0.01], PAN [+ 0.39]). For each period, CD4 + CD25 + FoxP3 + Tregs showed the most dramatic inverse effect, with D3 to D5 showing the most change (MFC: IRE [− 0.18], PAN [+ 0.39]). Also, CD4 + CD25 + FoxP3 − Tregs showed an inverse effect between D3 and D5 (MFC: IRE [− 0.25], PAN [+ 0.49]). Altogether, the Treg trend was inversely affected by the in situ IRE procedure, with the greatest cumulative significant change for all three Treg subsets between D3 and D5 (MFC ± SEM: IRE [− 0.24 ± 0.05], PAN [+ 0.37 ± 0.02]; p = 0.016).

Conclusions

The study data suggest that in situ IRE procedure-mediated Treg attenuation between POD3 and POD5 can provide a clinical window of opportunity for potentiating clinical efficacy in combination with immunotherapy.

Notes

Acknowledgment

This study was funded by the Division of Surgical Oncology, Hiram C. Polk Jr, MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202. No outside funding was received.

Conflict of interest

Robert C. G. Martin is a paid consultant for AngioDynamics. The remaining authors have no conflicts of interest.

Supplementary material

10434_2018_7144_MOESM1_ESM.docx (104 kb)
Levels of different subsets of CD4 + regulatory T cells: Box plot showing levels of different regulatory T cells subsets (Tregs) at different time points i.e. PreOP, D1, D3 and D5. All 4 time point specimens for each patient were processed and analyzed together, at the same time, using flowcytometry. PreOP = before surgery, D1 = POD1, D3 = POD3, D5 = POD5. Solid line represent median and dotted line represent mean. Supplementary material 1 (DOCX 104 kb)

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Copyright information

© Society of Surgical Oncology 2019

Authors and Affiliations

  • Harshul Pandit
    • 1
    • 2
  • Young K. Hong
    • 1
  • Yan Li
    • 1
  • Jack Rostas
    • 1
  • Zachary Pulliam
    • 1
  • Su Ping Li
    • 1
  • Robert C. G. Martin
    • 1
    • 2
  1. 1.Division of Surgical Oncology, Hiram C. Polk Jr. M.D. Department of SurgeryUniversity of Louisville School of MedicineLouisvilleUSA
  2. 2.Department of Pharmacology & ToxicologyUniversity of Louisville School of MedicineLouisvilleUSA

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